Macrocyclic and acyclic chelating agents have been employed for biomedical, environmental, and radiopharmaceutical applications such as magnetic resonance (MR) and positron emission tomography (PET) imaging and iron chelation therapy (ICT) and antibody targeted radiation therapy (Radioimmunotherapy, RIT) of cancer and nuclear remediation. Research efforts have been directed towards development of effective metal binding chelating agents, a critical component for such applications.
RIT holds great promise for treatment of many diseases including cancers, evidenced by Zevalin® (1B4M-DTPA) therapy. However, active clinical exploration of RIT using a variety of antibodies and cytotoxic radionuclides has been challenged by the absence of adequate bifunctional ligands that can bind the radionuclides with clinically acceptable kinetics and in vivo stability. The currently available bifunctional ligands, C-DOTA and C-DTPA analogues have limitations such as slow kinetics and low complex stability in vivo.
A sensitive diagnostic modality, positron emission tomography (PET) has been demonstrated to give highly sensitive detection and staging of various cancers. PET is known to provide imaging of solid tumors with better sensitivity, resolution, and quantification as compared to gamma ray and SPECT. Although various antibody or peptide conjugates based on TETA, DOTA, or CB-TE2TA radiolabeled with a radioactive metal have been explored for PET imaging of solid tumors in the preclinical settings, the currently available metal binding chelators do not present optimal chelation chemistry with the metals. Development of bifunctional ligand to rapidly and stably bind a radionuclide will allow for targeted and highly sensitive PET imaging of cancers.
MRI, a non-invasive and high resolution imaging technique has become a powerful cancer diagnostic technique. The paramagnetic Gd(II) complexes available in the clinic including DOTA and DTPA are the first generation of clinically approved MR contrast agents. However, Gd(DTPA) and Gd(DOTA) are non-specific contrast agents with extracellular distribution and have the disadvantages of low relaxivity, low tissue specificity, and rapid clearance. The contrast agents with high relaxitivty and tissue-specificity are required for sensitive MRI to the targeted tissues. Considerable research efforts have been made to develop contrast agents with high target-specificity and relaxivity.
Internal contamination with radionuclides that can occur during a nuclear accident or attack can lead to life-threatening diseases, and the radiocontaminants present in the human body must be rapidly and safely eliminated. Research efforts have been made to develop chelators as decorporation agents that can efficiently remove radionuclides from the body. Two metal complexes of diethylenetriaminepentaacetic acid (DTPA), Ca(II)-DTPA and Zn(II)-DTPA are clinically available as decorporation agents of diverse radioactinides including 241Am, 252Cf, 141Ce, and 144Ce, 238Pu, 239Pu, and 244Cm. DTPA is known to display rapid complexation kinetics with a wide range of radioactive metals. However, low binding selectivity, zinc stripping, poor kinetic stability, and poor aqueous solubility of DTPA limits its practical use for biomedical applications.
Development of better drugs for targeted therapy and imaging of cancers is a critical need. Multifunctional nanomedicines as theranostic drugs and dual modality diagnostics are expected to provide targeted therapy and sensitive imaging of the cancers. Although multifunctional theranostic and dual imaging technology is available in the clinic, less progress has been made on development of multifunctional chelators that can tightly and rapidly hold biologically important metals. There is thus a continuing need for improved chelators and multifunctional ligands, such as for use as discussed above.